Broader uptake of single-pill combination (SPC) therapies—polypills—to simplify primary or secondary prevention of cardiovascular disease could have a huge impact on a global scale in the coming decades, according to a modeling study.
Depending on how they’re rolled out, these medications could help prevent 29 to 51 million deaths and 72 to 130 million nonfatal MIs, strokes, and cases of heart failure by 2050, researchers led by David Watkins, MD (University of Washington, Seattle), report in a study published online ahead of the July 22, 2025, issue of JACC.
The most substantial impacts would be felt in countries that have large populations and suboptimal current use of therapies for CVD prevention.
The study helps in “framing the agenda for how important this is amongst all the things you can do for cardiovascular disease,” Watkins told TCTMD. “We try to contextualize how big of a reduction in cardiovascular disease you can get with these therapies versus others and really make the case that this represents an important step in improving implementation of evidence-based care.”
Anubha Agarwal, MD (WashU Medicine, St. Louis, MO), who was not involved in the study, said it comes at an opportune time because the United Nations General Assembly’s fourth high-level meeting on noncommunicable diseases will take place in September. That meeting will likely provide new global targets for CVD prevention.
In that context, this is “a phenomenal paper because it really demonstrates the unrealized potential of single-pill combination therapies, including a blood pressure-lowering agent and a lipid-lowering agent, as being one tool in our toolbox to fight the rising cardiovascular disease epidemic and the potential global impact if SPCs were really integrated into care globally and particularly in [low- and middle-income country] settings,” Agarwal commented to TCTMD.
Modeling the Potential Benefits of Polypills
Though there are numerous safe and effective medications for the primary and secondary prevention of CVD, including lipid-lowering therapies, antihypertensives, and antiplatelets, use is low in many parts of the world. Polypills have been proposed as a strategy to simplify treatment, help improve uptake and adherence, and ultimately reduce the burden CVD.
“Unfortunately, widespread adoption and implementation has simply not occurred because of numerous barriers to bringing new SPC therapies to market and the resistance of important institutions to new paradigms for CVD prevention,” Watkins et al say.
Despite the resistance, there are accumulating data on their effectiveness. A 2021 meta-analysis showed that fixed-dose combination therapy significantly reduced the risk of a first major CV event in a primary prevention setting, with an even greater effect when aspirin was included. Subsequently, in the SECURE trial, a polypill incorporating aspirin, an ACE inhibitor, and a statin cut major cardiovascular events compared with usual care in patients who had recently had an MI, providing support for SPC therapy in a secondary prevention setting.
This evidence contributed to the World Health Organization’s decision to add SPC therapies for CVD prevention to its list of essential medicines in 2023.
In the current study, Watkins and his colleagues modeled the potential effect of rolling out SPC therapies for CVD prevention more widely across 182 countries between 2023 and 2050 and compared that with what would be expected if current practices (no use of these medications) continued.
The researchers evaluated implementation of SPC therapies in two scenarios:
- Targeted: Efforts would be focused on patients who are already aware of their high risk of CVD and are receiving care but are not receiving optimized therapy. This assumes 15% of eligible patients would be on a polypill in 2050.
- Population: Implementation would be expanded to people over age 55 who have an intermediate-to-high risk of CVD but are not yet receiving care. This assumed 35% of eligible patients would be on SPC therapy in 2050.
“We try to be really conservative and say this is essentially not going to change all of cardiovascular medicine but will be part of the tool kit,” Watkins said.
The analysis relied on SPC effectiveness and safety data from the 2021 meta-analysis.
Worldwide, the estimated effect of ramping up polypill use by 2050 would be similar to what would be achieved by the near-elimination of tobacco smoking (about 20 million deaths avoided) or providing antihypertensive drug therapy coverage of 80% (about 53 million deaths prevented), the investigators say.
Our resistance as clinicians to more simple forms of treatment is actually doing harm in itself . . . by not introducing technologies that improve uptake and adherence. David Watkins
Countries in South and East Asia and the Pacific region would be expected to have the most to gain through greater use of SPC therapies due to their large populations and high age-specific CVD rates. The impact would be less in North America due to the relatively high current use of CVD prevention therapies.
These SPC products would also be expected to reduce all-cause premature mortality (before age 70 years) by 2.0% in the targeted scenario and 3.2% in the population scenario, “facilitating achievement of global health targets,” Watkins et al write, alluding to the “50 by 50” goal of halving the probability of premature death by 2050 laid out by the Lancet Commission on Investing in Health.
The projected gains provided by polypills were not accompanied by major increases in adverse effects, with the researchers reporting that there was not a higher rate of fatal adverse events offsetting the number of CVD deaths that could be avoided. They estimated, however, that between 2023 and 2050, there would be 150 to 340 million additional cases of dizziness, including some related to hypotension, and—if SPC therapies containing aspirin were used—up to 27 million additional cases of nonfatal GI bleeding.
“These are side effects that can easily be managed by downtitration or discontinuation of therapy, so I think these are incredibly safe drugs,” Agarwal said. “And the benefit to be gained in potential lives saved is much greater than the potential risk of a greater absolute number of adverse effects.”
A Starting Point
Modeling studies like these, Agarwal said, “are really helpful in understanding the potential impact, with the caveat that there’s a lot of information that may be missing from models that can’t be captured.”
In addition to these types of analyses, “there’s a whole range of additional research that is needed, including implementation science to understand how you integrate these therapies into multilevel strategies that are context specific,” she added. “I think the next question really for the global community is, how do we realize this potential? What comes next?”
One obstacle to overcome is the general failure thus far of bringing these types of therapies to the market. In the US, there are currently no SPCs containing lipid-lowering and antihypertensive therapies available (although the Food and Drug Administration recently approved a polypill containing three BP-lowering medications). Agarwal indicated that pharmaceutical companies may be wary of developing SPC therapies because profitability is questionable when generic medications are involved, and this, she said, has led to a lack of large-scale investments in these pills.
[Unlike for HIV/AIDS], we just don’t see that level of coordination, political muscle, and financing available for CVD. Anubha Agarwal
Agarwal contrasted the situation around polypills for CVD prevention with that around therapies for HIV/AIDS. In the latter case, there was strong political will to find solutions; coordination among scientists, the public health community, and politicians; and international funding.
“We just don’t see that level of coordination, political muscle, and financing available for CVD,” she said.
There are three main issues standing in the way of greater use of SPC therapies for CVD prevention, Watkins said, pointing to the dearth of interested manufacturers, low demand from national governments, and resistance among some clinicians who want to have more control about titrating individual medications.
“Getting more cardiologists and thought leaders in the field coming around to the idea of using them I think would be really important,” he said, underscoring that changes are needed in how CVD prevention is being practiced.
“The main message and the main motivation for this is that for many people, they’re just not accessing care or not even initiating care in the first place,” Watkins said. “And so our resistance as clinicians to more simple forms of treatment is actually doing harm in itself, on the order of tens of millions of preventable deaths a year, by not introducing technologies that improve uptake and adherence.”
He argued that “rolling out simpler approaches that use single-pill combinations and trying to get more pills into more people, provided the risk assessment is favorable, could be really game-changing for improving uptake of especially primary prevention efforts.”
In an accompanying editorial, Anthony Rodgers, MBChB, PhD (University of New South Wales, Australia, and Imperial College London, England), and colleagues say the paper “provides an urgent and timely message” about the potential for SPC therapies to fill gaps in CVD prevention.
“Future work should embrace the complexity of real-world implementation,” they continue, “and recognize that realizing this enormous opportunity—comparable to tobacco control and improved food environments—requires our decisive and collective action.”
